DEVELOPMENT OF A RECEPTOR-INTERACTION MODEL FOR SEROTONIN 5-HT2 RECEPTOR ANTAGONISTS - PREDICTING SELECTIVITY WITH RESPECT TO DOPAMINE D-2 RECEPTORS

A receptor-interaction model for serotonin 5-HT2 receptor antagonists has been developed by conformational analysis with molecular mechanics (MM2(91)) and superimposition studies of serotonin 5-HT2 receptor antagonists. Substituted 3-(4-piperidinyl)-, 1-(4-piperidinyl)-, 3-(1,2,3,6-tetrahydropyridin-4-yl)-, and 1-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles, substituted 3-(4-fluorophenyl)-1-(4-piperazinyl)indans, cyproheptadine derivatives, ritanserin, and danitracene have been used as bases for the model. Other serotonin 5-HT2 receptor antagonists, such as ketanserin and MDL 11,939, are well accommodated into the model. Comparison of the model with a recently described receptor-interaction model for dopamine D-2 receptor antagonists suggests a common pharmacophore for dopamine D-2 and serotonin 5-HT2 receptor antagonists. Important steric differences between 5-HT2 receptor antagonists with additional high affinity for dopamine D-2 receptors and serotonin 5-HT2 receptor antagonists with high selectivity versus D-2 receptors are described. The geometry of the receptor-interaction model described is significantly different from that of a recently reported receptor-interaction model for 5-HT2 receptor agonists and antagonists developed by use of (+)-LSD as a template, suggesting the existence of two binding modes at the 5-HT2 receptor.